Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study

Anne M Drewry, Enyo A Ablordeppey, Ellen T Murray, Evan R Beiter, Andrew H Walton, Mark W Hall, Richard S Hotchkiss, Anne M Drewry, Enyo A Ablordeppey, Ellen T Murray, Evan R Beiter, Andrew H Walton, Mark W Hall, Richard S Hotchkiss

Abstract

Background: Identifying patients in the immunosuppressive phase of sepsis is essential for development of immunomodulatory therapies. Little data exists comparing the ability of the two most well-studied markers of sepsis-induced immunosuppression, human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-ɑ) production, to predict mortality and morbidity. The purpose of this study was to compare HLA-DR expression and LPS-induced TNF-ɑ production as predictors of 28-day mortality and acquisition of secondary infections in adult septic patients.

Methods: A single-center, prospective observational study of 83 adult septic patients admitted to a medical or surgical intensive care unit. Blood samples were collected at three time points during the septic course (days 1-2, days 3-4, and days 6-8 after sepsis diagnosis) and assayed for HLA-DR expression and LPS-induced TNF-ɑ production. A repeated measures mixed model analysis was used to compare values of these immunological markers among survivors and non-survivors and among those who did and did not develop a secondary infection.

Results: Twenty-five patients (30.1 %) died within 28 days of sepsis diagnosis. HLA-DR expression was significantly lower in non-survivors as compared to survivors on days 3-4 (p = 0.04) and days 6-8 (p = 0.002). The change in HLA-DR from days 1-2 to days 6-8 was also lower in non-survivors (p = 0.04). Median HLA-DR expression decreased from days 1-2 to days 3-4 in patients who developed secondary infections while it increased in those without secondary infections (p = 0.054). TNF-ɑ production did not differ between survivors and non-survivors or between patients who did and did not develop a secondary infection.

Conclusions: Monocyte HLA-DR expression may be a more accurate predictor of mortality and acquisition of secondary infections than LPS-stimulated TNF-ɑ production in adult medical and surgical critically ill patients.

Keywords: Immunosuppression; Monocytes; Mortality; Sepsis.

Figures

Fig. 1
Fig. 1
Gating strategy for determining monocyte HLA-DR levels. A monocyte gate was created by first gating upon forward and side scatter cell properties (upper right panel) and then further refining the monocyte gate by determining positivity for CD14 (lower left panel). Geometric mean fluorescence intensity (GMFI) data were then collected from the monocyte population in the HLA-DR channel (PE) (lower right panel) and compared against a Quantibrite Bead Reference (Becton Dickinson, San Jose, CA, USA) (upper left panel) to yield average per cell HLA-DR intensity. HLA human leukocyte antigen, PE phycoerythrin
Fig. 2
Fig. 2
Flow diagram of included patients and reasons for patient exclusion. HBV hepatitis B virus, HBC hepatitis C virus
Fig. 3
Fig. 3
Median and interquartile range of (a) HLA-DR expression in survivors and non-survivors, (b) LPS-induced TNF-ɑ production in survivors and non-survivors, (c) HLA-DR expression in those who did and did not develop secondary infections, and (d) LPS-induced TNF-ɑ production in those who did and did not develop secondary infections. HLA human leukocyte antigen, TNF-ɑ tumor necrosis factor alpha
Fig. 4
Fig. 4
Plot of correlation between log-transformed HLA-DR expression and LPS-induced TNF-ɑ production for each measured time point (days 1–2, days 3–4, and days 6–8). HLA human leukocyte antigen, TNF-ɑ tumor necrosis factor alpha

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